The invention refers to novel 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivatives, a pharmaceutical composition containing the same, and a process for the preparation of the active ingredient.
More specifically, the invention refers to novel 8-substituted-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine derivatives of the formula I 
wherein
X represents a carbonyl group or a methylene group, and
R1 stands for a hydrogen atom, a hydroxy group, a C1-4 alkoxy group, a C1-4 alkanoyloxy group, a (C1-4 alkyl)sulfonyloxy group or a group of the formula xe2x80x94NR4R5, wherein
R4 and R5 mean, independently, a hydrogen atom, a C1-4 alkoxy group, a C1-4 alkanoyl group or a C1-6 alkyl group which latter is optionally substituted by a saturated or unsaturated heterocyclic group having 5 or 6 members and comprising one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom as the heteroatom, or by an N-/phenyl-(C1-4 alkyl)/-N-(C1-4 alkyl)amino group, wherein the phenyl group is optionally substituted by 1 to 3 substituent(s), wherein the substituent consists of a C1-4 alkoxy group, or
R4 and R5 form with the adjacent nitrogen atom and optionally with a further nitrogen atom or an oxygen atom a saturated or unsaturated heterocyclic group having 5 to 10 members, or
X forms together with R1 a cyano group, a tetrazolyl group, a group of the formula xe2x80x94CHNOH, or a group of the formula xe2x80x94COR6, wherein
R6 means a hydroxy group, a C1-4 alkoxy group, a phenoxy group, a naphthyloxy group, or an amino group which latter is optionally substituted by a C1-4 alkyl group,
R2 stands for a nitro group, an amino group or a (C1-4 alkanoyl)amino group,
R3 represents a hydrogen atom, a C1-4 alkyl group, or a group of the formula xe2x80x94COR7, wherein
R7 represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkyl group substituted by 1 to 3 halo atom(s), a C1-4 alkoxy group, a phenoxy group, a pyridyl group, a phenyl group or a naphthyl group which two latter groups are optionally substituted by 1 to 3 substituent(s), or a group of the formula xe2x80x94(CH2)nxe2x80x94NR8R9, wherein
R8 and R9 represent, independently, a hydrogen atom, a C1-4 alkyl group optionally substituted by a phenyl group or a saturated heterocyclic group having 5 or 6 members and containing a nitrogen group or a nitrogen and an oxygen group, and said phenyl group is optionally substituted by 1 to 3 substituent(s), wherein the substituent consists of a C1-4 alkoxy group, or
R8 and R9 form, together with the adjacent nitrogen atom and optionally a further nitrogen or oxygen atom, a saturated or unsaturated hetero-cyclic group having 5 or 6 members and being optionally substituted by a phenyl group that is optionally substituted by 1 to 3 substituents, wherein the substituent consists of a halo atom or a C1-4 alkoxy group,
n has a value of 0, 1 or 2,
Y is a hydrogen atom, or a methyl group, or
Y forms together with R3 a valence bond between the carbon atom in position 8 and the nitrogen atom in position 7,
with the proviso that
1) if Y stands for a hydrogen atom or forms together with R3 a valence bond and X represents a methylene group, then R1 is other than a hydrogen atom, and
2) if Y stands for a hydrogen atom or a methyl group and R3 represents a C1-4 alkyl group or a group of the formula xe2x80x94COR7, then X is other than a methylene group,
and pharmaceutically suitable acid addition salts or quaternary ammonium derivatives thereof.
Several 2,3-benzodiazepine derivatives having biological activity are known.
Tofisopam i.e. 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine having anxiolytic effect is known from HU-P No. 155 572 and GB-P No. 1 202 579, respectively. The known compound does not comprise the ring system 1,3-dioxolo-/4,5-h//2,3/benzodiazepine.
From HU-P No. 186 760, 7,8-dihydro-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives having effect on the central nervous system are known, among others. The known compounds are prepared by reducing the corresponding 8-methyl-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine derivative.
Various substituted 8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives are known from HU-P No. 191 698 and the corresponding GB-P No. 2 162 184. The known compounds have antiaggressive and anxiolytic activities.
A novel process for the preparation of partly new 8-methyl-9H-1,3-dioxolo/4,5-h/-/2,3/benzodiazepine derivatives having antiaggressive activity is known from HU-P No. 191 702. According to the novel process, the suitably substituted 2-acetonyl-4,5-methylenedioxybenzophenone is reacted with an excess of hydrazine hydrate.
Further 7,8-dihydro-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives having antidepressant and antiparkinsonian activities are known from HU-P No. 206 719.
A physical form of (R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo/4,5-h//2,3/benzodiazepine useful as an AMPA antagonist is described in EP No. 699 678.
7-Acyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives having anticonvulsive and muscle-relaxant activity are known from EP No. 492 485.
Enantiomers of 7,8-dihydro-8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine are described in WO 95/01357. The known enantiomers are useful as intermediates in the synthesis of therapeutically active compounds.
In EP No. 699 677 a stereoselective process for producing known dihydro-2,3-benzodiazepine derivatives is described.
5-(4-Substituted phenyl)-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives are described in FR 2 566 774. The compounds have antiagressive activity.
In J. Am. Chem. Soc., 117, 12358-9 (1995) an enantioselective synthesis for the preparation of 7-acetyl-5-(4-aminophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo/4,5-h/-/2,3/benzodiazepine is described.
7-Acyl-5-(4-aminophenyl)-8-alkyl-7H-1,3-dioxolo/4,5-h//2,3/benzodiazepines are described in DE-P No. 44 28 835. The known compounds inhibit the AMPA receptors.
An enantioselective synthesis for the preparation of 7-acyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivatives is known from J. Chem. Sac. Perkin Trans I, 1995, 1423-1427.
Some of the 2,3-benzodiazepine derivatives elicit their effect through the non-competitive inhibition of the AMPA/kainate receptors /Donevan, S. D. et al., J. Pharmacol. Exp. Ther., 271, 25-29 (1994)/.
From the literature it is known that AMPA/kainate receptors play an important role in the acute and chronic diseases of the central nervous system. Through the inhibition of these receptors, muscle relaxant, neuro-protective and spasm inhibiting effects can be achieved /Vizi, E. S. et al., CNS Drug Reviews, 2, 91-126 (1996); Lees, G. L., CNS Drugs, 5, 51-74 (1996)/.
The aim of the invention is to prepare novel 2,3-benzodiazepine derivatives that are more effective than the known 2,3-benzodiazepine derivatives.
It was found that the above aim is achieved by the novel 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives which havexe2x80x94due to their non-competitive AMPA/kainate effectxe2x80x94considerable muscle relaxant, neuroprotective and anticonvulsive activities.
Thus, the novel compounds can be employed for the treatment of any diseases (such as epilepsy, diseases resulting in muscle spasm, various neurodegenerative diseases, stroke) in which the inhibition of the AMPA/kainate receptors is favourable.
In the description and Claims, in the definition of the substituents, under a C1-4 alkoxy group primarily a methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy group, preferably a methoxy group is meant.
A C1-4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group. Preferably, a C1-4 alkyl group is a methyl or an ethyl group.
A C1-6 alkyl group can be, in addition to alkyl groups listed above, for example a n-pentyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group etc.
A C1-4 alkanoyl group is, primarily, a formyl, acetyl or n-propionyl group. Preferably, a C1-4 alkanoyl group is an acetyl group.
Similarly, a C1-4 alkanoyloxy group is, primarily, a formyloxy, acetyloxy or n-propionyloxy group.
Under a saturated or unsaturated heterocyclic group having 5 or 6 members and comprising one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom as the heteroatom, for example a pyrrolidinyl, piperidinyl, piperazinyl, imidazolyl or morpholino group is meant. Suitably, the other nitrogen atom of the piperazinyl group is substituted.
When the substituents R4 and R5 form with the adjacent nitrogen atom a saturated or unsaturated heterocyclic group having 5 to 10 members, said heterocyclic group contains one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom as the heteroatom, and it consists of one ring or two condensed rings. The heterocyclic ring(s) contain(s) no double bond or one or more double bond(s). The above heterocyclic group is for example a pyrrolidinyl, imidazolyl, piperidinyl, pyridyl, morpholino, piperazinyl or 1,5-diazabicyclo/4.3.0/non-5-enyl group. Suitably, one of the nitrogen atoms of the piperazinyl group is substituted.
Under a pharmaceutically suitable acid addition salt an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc. or with a pharmaceutically suitable organic acid such as formic acid, acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid etc. is meant.
A quaternary ammonium derivative is a derivative wherein one of the nitrogen atoms of a compound of the formula I is present in a quaternerized form.
The invention includes any isomers of the compounds of the formula I and the mixtures thereof.
Under the isomers of the compounds of the formula Ixe2x80x94due to the presence of at least one chiral centre both enantiomers, andxe2x80x94because of isomerisms that exist in case of certain substitutionsxe2x80x94the isomers E and Z, diastereomers, tautomeric forms, and the mixtures thereof such as the racemate are meant.
A preferred subgroup of the compounds of the formula I consists of the 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives and pharmaceutically suitable acid addition salts and quaternary ammonium derivatives thereof, wherein in the formula I
X represents a carbonyl group or a methylene group, and
R1 stands for a hydrogen atom, a hydroxy group, a methoxy group, an acetoxy group, a methylsulfonyloxy group or a group of the formula xe2x80x94NR4R5, wherein
R4 and R5 mean, independently, a hydrogen atom, a methoxy group, an acetyl group or a C1-4 alkyl group which latter is optionally substituted by a morpholino or a dimethoxyphenylethyl-N-(methyl)amino group, or
R4 and R5 form with the adjacent nitrogen atom and optionally with a further nitrogen atom or an oxygen atom a saturated or unsaturated heterocyclic group having 5 to 9 members, or
X forms together with R1 a cyano group, a tetrazolyl group or a group of the formula xe2x80x94CHNOH,
R2 stands for a nitro group or an amino group,
R3 represents a hydrogen atom or an acetyl group,
Y is a hydrogen atom, or
Y forms together with R3 a valence bond between the carbon atom in position 8 and the nitrogen atom in position 7.
with the proviso that
1) if Y stands for a hydrogen atom or forms together with R3 a valence bond and X represents a methylene group, then R1 is other than a hydrogen atom, and
2) if Y stands for a hydrogen atom or a methyl group and R3 represents a C1-4 alkyl group pr a group of the formula xe2x80x94COR7, then X is other than a methylene group.
Within the above subgroup, especially preferred compounds of the invention consist of the following 8-substituted-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine derivatives and pharmaceutically suitable acid addition salts and quaternary ammonium derivatives thereof: 5-(4-aminophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine-8-carboxylic amide, 5-(4-aminophenyl)-8-cyano-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine, 5-(4-aminophenyl)-8-(5-tetrazolyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine.
A further preferred subgroup of the compounds of the invention consists of the 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivatives of the formula I, wherein
R3 represents a hydrogen atom or a group of the formula xe2x80x94COR7, wherein
R7 stands for a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group substituted by 1 to 3 halo atom(s), or a group of the formula xe2x80x94(CH2)nxe2x80x94NR8R9, wherein
R8 and R9 mean, independently, a hydrogen atom, a C1-4 alkyl group optionally substituted by a phenyl group or a morpholino group, and the phenyl group is optionally substituted by one or two methoxy group(s), or
R8 and R9 form, together with the adjacent nitrogen atom and optionally a further nitrogen or oxygen atom a saturated or unsaturated hetero-cyclic group having 5 or 6 members. and being optionally substituted by a phenyl group that is optionally substituted by a halo atom or a methoxy group,
n has a value of 0, 1 or 2,
X forms together with R1 a cyano group or a group of the formula xe2x80x94COR6, wherein
R6 represents a hydroxy group or an amino group,
Y stands for a methyl group,
R2 is a nitro group, an amino group, or a (C1-4 alkanoyl)amino group,
and pharmaceutically suitable acid addition salts thereof.
Within the above subgroup, suitable compounds of the invention consist of the 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivatives of the formula I, wherein
R3 represents a hydrogen atom or a group of the formula xe2x80x94COR7, wherein
R7 stands for a hydrogen atom, a C1-4 alkyl group, a C1-2 alkyl group substituted by a chloro atom, a trifluoromethyl group, a trichloromethyl group or a group of the formula xe2x80x94(CH2)nxe2x80x94NR8R9, wherein
R8 and R9 represent, independently, a hydrogen atom, a C1-2 alkyl group optionally substituted by a phenyl group or a morpholino group, and the phenyl group is optionally substituted by two methoxy groups, or
R8 and R9 form, together with the adjacent nitrogen atom and optionally a further nitrogen or oxygen atom a pyridinyl, pyrrolidinyl, morpholino or piperazinyl group, wherein the piperazinyl group is substituted by a fluorophenyl or a methoxyphenyl group,
n has a value of 0, 1 or 2,
X forms together with R a cyano group,
R2 means an amino group or a (C1-4 alkanoyl)-amino group,
Y stands for a methyl group,
and pharmaceutically suitable acid addition salts thereof.
Especielly preferred compounds of the invention consist of the 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives of the formula I, wherein
R2 represents an acetylamino or a propionyl-amino group,
R1, R3, X and Y are as defined in claim 5,
and pharmaceutically suitable acid addition salts thereof.
The 8-substituted-9H-l,3-dioxolo-/4,5-h//2,3/benzodiazepine derivatives of the invention are prepared by the following methods:
a) for the preparation of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine of the formula II 
xe2x80x83being within the scope of the compounds of the formula I, 8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine is reacted with an oxidizing agent; or
b) for the preparation of 5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine-8-carboxylic acid of the formula III 
xe2x80x83being within the scope of the compounds of the formula I, 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine of the formula II is reacted with an oxidizing agent; or
c) for the preparation of compounds of the formula I, wherein R1 is an imidazolyl group, R2 represents a nitro group, X stands for a carbonyl group, and Y forms together with R3 a valence bond, 5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine-8-carboxylic acid of the formula III is reacted with 1,1xe2x80x2-carbonyldiimidazole; or
d) for the preparation of compounds of the formula I, wherein R1 is a group of the formula xe2x80x94NR4R5, R2 represents a nitro group, X stands for a carbonyl group, Y forms together with R3 a valence bond, R4 and R5 are as defined in connection with the formula I, 5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine-8-carboxylic acid of the formula III or a reactive derivative thereof of the formula IV 
wherein Y1 is a leaving group, is reacted with an amine of the formula V 
wherein R4 and R5 are as stated above; or
e) for the preparation of compounds of the formula I, wherein R1 is a C1-4 alkoxy group, R2 represents a nitro group, X stands for a carbonyl group, Y forms together with R3 a valence bond, 5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine-8-carboxylic acid of the formula III is esterified with a C1-4 alkanol; or
f) for the preparation of compounds of the formula I, wherein R1 is a (C1-4 alkyl)sulfonyloxy group, R2 represents a nitro group, X stands for a methylene group, Y forms together with R3 a valence bond, 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine of the formula II is reacted with a reducing agent, and the 8-(hydroxymethyl)-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine obtained is reacted with a (C1-4 alkyl)sulfonyl halide; or
g) for the preparation of compounds of the formula I, wherein R1 represents a C1-4 alkoxy group, a C1-4 alkanoyloxy group or a group of the formula xe2x80x94NR4R5, R2 stands for a nitro group, Y forms together with R3 a valence bond, R4 and R5 are as stated in connection with formula I, 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine of the formula II is reacted with a reducing agent, and the 8-(hydroxymethyl)-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine obtained or a reactive alkylating derivative thereof of the formula VI 
xe2x80x83wherein Q stands for a leaving group, is reacted with a C1-4 alkanol, a C1-4 alkanecarboxylic acid or a reactive acylating derivative thereof or an amine of the formula V, wherein R4 and R5 are as stated above; or
h) for the preparation of a compound of the formula I, wherein X forms together with R1 a group of the formula xe2x80x94CHNOH, R2 represents a nitro group, Y forms together with R3 a valence bond, 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine of the formula II is reacted with hydroxylamine; or
i) for the preparation of a compound of the formula I, wherein X forms together with R1 a cyano group, R2 represents a nitro group, Y forms together with R3 a valence bond, 8-(hydroxyiminomethyl)-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine is reacted with a dehydrating agent; or
j) for the preparation of a compound of the formula I, wherein X forms together with R1 a tetrazolyl group, R2 represents a nitro group, Y forms together with R3 a valence bond, 8-cyano-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine is reacted with an alkaline metal azide; or
k) for the preparation of 7,8-dihydro compounds of the formula VI being a narrower group of the compounds of the formula I, wherein X represents a carbonyl group or a methylene group, and R1 is as defined in connection with formula I, a compound of the formula VII 
wherein X and R are as stated above, is reacted with a reducing agent; or
l) for the preparation of 7,8-dihydro-7-acyl derivatives of the formula VIII 
xe2x80x83being a narrower group of the compounds of the formula I, wherein X represents a carbonyl group or a methylene group, R1 is as stated in connection with formula I, R3 stands for a C1-4 alkanoyl group, a 7,8-dihydro derivative of the formula VI, wherein X and R1 are as defined above, is reacted with a C1-4 alkanecarboxylic acid or a reactive acylating derivative thereof; or
m) for the preparation of compounds of the formula I, wherein R1 is a group of the formula xe2x80x94NR4R5, R2 represents a nitro group, X stands for a carbonyl group or a methylene group, one of R4 and R5 represents a C1-4 alkanoyl group, while the other is as defined in connection with formula I, Y means a hydrogen atom and in this case R3 stands for a C1-4 alkanoyl group, or Y forms together with R3 a valence bond, a compound of the formula I, wherein R1 is a group of the formula xe2x80x94NR4R5, wherein one of R4 and R5 means a hydrogen atom, while the other is as defined above, X, R2, Y and R3 are as stated above, is reacted with a C1-4 alkanecarboxylic acid or a reactive acylating derivative thereof;
n) for the preparation of compounds of the formula I, wherein Y represents a methyl group, xe2x80x94Xxe2x80x94R1 stands for a cyano group, R3 is a hydrogen atom, and R2 means a nitro group, the compound of the formula IX 
xe2x80x83is reacted with hydrogen cyanide; or
o) for the preparation of compounds of the formula I, wherein Y represents a methyl group, R3 stands for a hydrogen atom, R2 means a nitro group and xe2x80x94Xxe2x80x94R1 represents a group of the formula xe2x80x94COR6, wherein R6 is as defined in connection with the formula I, the compound of the formula X 
xe2x80x83is hydrolyzed with a mineral acid, and the carboxylic acid obtained is optionally converted to an ester or a carboxylic amide; or;
p) for the preparation of compounds of the formula I, wherein Y represents a methyl group, xe2x80x94Xxe2x80x94R1 stands for a cyano group or a group of the formula xe2x80x94COR6, R2 means a nitro group, R3 is a C1-4 alkyl group, and R6 is as defined in connection with the formula I, a compound of the formula I, wherein Y, xe2x80x94Xxe2x80x94R1 and R2 are as stated above, R3 represents a hydrogen atom, is reacted with a (C1-4 alkyl)halide; or
r) for the preparation of compounds of the formula I, wherein Y represents a methyl group, xe2x80x94Xxe2x80x94R1 stands for a cyano group or a group of the formula xe2x80x94COR6, R2 means a nitro group, R3 is a group of the formula xe2x80x94COR7, R7 represents a group of the formula xe2x80x94(CH2)nxe2x80x94xe2x80x94NR8R9, R6, R8, R9 and n are as defined in connection with the formula I, a compound of the formula XI 
wherein xe2x80x94Xxe2x80x94R1, R2 and n are as stated above, X1 is a leaving group, preferably a chloro atom, is reacted with an amine of the formula HNR8 R9;
and, if desired, an obtained compound of the formula I, wherein R2 represents a nitro group, R1, R3, X and Y are as defined in connection with formula I, is transformed into a compound of the formula I, wherein R2 represents an amino group, by reduction;
and, if desired, an obtained compound of the formula I, wherein R2 represents an amino group, R1, R3, X and Y are as stated in connection with formula I, is reacted with a C1-4 alkanecarboxylic acid or a reactive acylating derivative thereof;
and, if desired, an obtained base of the formula I is converted to a pharmaceutically suitable acid addition salt or liberated from the acid addition salt;
and, if desired, an obtained compound of the formula I or pharmaceutically suitable acid addition salt thereof is converted to a quaternary ammonium derivative.
In process a) of the invention, the reaction is performed in a manner known in itself in the preparation of aldehydes /Houben-Weyl: Methoden der Organischen Chemie, Aldehyde, Band E3, Georg Thieme Verlag, Stuttgart, 1983/.
A preferred oxidizing agent is selenium(IV) oxide.
In process b) of the invention, the reaction is conducted in a manner known in itself in the preparation from carboxylic acids from aldehydes /Houben-Weyl: Methoden der Organischen Chemie, Carbonsaure-Derivate, Band E5, Georg Thieme Verlag, Stuttgart, 1985; Saul Patai: The chemistry of acid derivatives, John Wiley and Sons, New York/.
In processes c), d) and e) of the invention, the reactions are carried out in a manner known in itself in the transformations of carboxylic acids /Houben-Weyl: Methoden der Organischen Chemie, Carbonsaure und Carbonsaure-Derivate, Band E5, Georg Thieme Verlag, Stuttgart, 1985/.
In processes f) and g) of the invention, the reactions are performed in a manner known in itself in the transformation of oxo compounds to alcohols /Houben-Weyl: Methoden der Organischen Chemie, Alkohole, Band VI, Georg Thieme Verlag, Stuttgart, 1979/. The hydroxy compound formed is reacted also in a manner known in itself with an alkylsulfonyl halide, preferably methylsulfonyl chloride in case of process f); in case of process g), the alkylsulfonyl ester of the hydroxy compound is reacted with an amine or the hydroxy compound is acylated for example with the corresponding alkanecarboxylic anhydride.
In processes h), i) and j) of the invention, the reactions arre carried out in a manner known in itself in the transformations of oxo compounds /Houben-Weyl: Methoden der Organischen Chemie, Carbonsaure und Carbonsaure-Derivate, Band E5, Georg Thieme Verlag, Stuttgart, 1985; Houben Weyl: Methoden der Organischen Chemie, Heterane, Band III, part 4, Georg Thieme Verlag, Stuttgart, 1994/.
In process k) of the invention, the reduction is performed in a manner known in itself /Houben-Weyl: Methoden der organischen Chemie, Band IV, Reduction, Georg Thieme Verlag, Stuttgart, 1989/.
In processes f), g) and k) of the invention, the reducing agent is preferably sodium tetrahydroborate.
It is to be noted that in case of reducing a compound of the formula I, wherein X represents a carbonyl group, Y forms together with R3 a valence bond, R2 stands for a nitro group, using an equimolar amount of sodium tetrahydroborate, only the carbonyl group is reduced. In the presence of a large excess of sodium tetrahydroborate, in addition to the reduction of the carbonyl group, the double bond between the ring nitrogen in position 7 and the ring carbon atom in position 8 becomes saturated, too.
In processes l) and m) of the invention, the acylation reactions are carried out, in general, using a reactive acylating derivative of the C1-4 alkanecarboxylic acid such as acid halide, acid anhydride or an active ester, at a temperature from xe2x88x9220 to +150xc2x0 C. preferably in the presence of an acid binding agent and/or pyridine, in the presence or absance of an organic solvent /Houben-Weyl: Methoden der Organischen Chemie, Carbonsaure und Carbonsaure-Derivate, Band E5, Georg Thieme Verlag, Stuttgart, 1985; S. Patai: The chemistry of amides, Interscience Publishers, 1970/.
In process n) of the invention, the reaction of the compound of the formula IX and hydrogen cyanide is carried out in a manner known from the literature /Houben-Weyl: Methoden der organischen Chemie, Band VIII, Georg Thieme Verlag, Stuttgart/.
The 8-methyl-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivative of the formula IX can be prepared by a method that is analogous with the process described in HU-P No. 191 702.
In process o) of the invention, the cyano group of the compound of the formula X can be hydrolized in a manner known in itself, preferably in the presence of a mineral acid /S. Patai: The chemistry of the cyano group/.
In process p) of the invention, the nitrogen atom in position 8 of the compound of the formula I can be acylated in a manner known in itself, in general, with an acid chloride, an acid anhydride or a chlorocarbonate ester, optionally in the presence of an acid binding agent, in the presence or absence of a solvent, at a temperature from xe2x88x9220 to +150xc2x0 C.
For the preparation of carbamoyl derivatives, the acylated derivative obtained by using an active chlorocarbonate ester is reacted with an amino compound, or a compound of the formula I, wherein R represents a hydrogen atom, is reacted directly with the corresponding isocyanate.
In process r) of the invention, compounds of the formula I, wherein the carbon atom in position 8 is substituted by a group of the formula xe2x80x94COxe2x80x94(CH2)nxe2x80x94NR4R5, can be suitably prepared by reacting the corresponding compound of the formula XI, wherein R1, R2 and n are as stated in connection with formula I, X stands for a leaving group, preferably a chloro atom, with an amine of the formula HNR4R5, wherein R4 and R5 are as defined in connection with formula I. The compound of the formula XIcan be prepared by acylating a compound of the formula I, wherein R means a hydrogen atom. The reactions given above are performed in a manner known from the art /Houben-Weyl: Methoden der Organischen Chemie, Band XI, G. Thieme Verlag, Stuttgart, 1957; S. Patai: The chemistry of amino group, Interscience Publishers, 1968/.
The nitro group of the compounds of the formula I can be converted to an amino group by reduction in a manner known in itself. The reduction can be performed for example with tin(II) chloride or in the presence of a catalyst using a hydrogen source. For example, the catalyst is Raney nickel, palladium or platinum oxide, the hydrogen source consists of, for example, gaseous hydrogen, hydrazine, hydrazine hydrate, formic acid, trialkylammonium formate or an alkali metal formate.
In case of compounds of the formula I, wherein R2 represents an amino group, the latter group can be acylated with a C1-4 alkanecarboxylic acid in a manner known in itself. The acylation reaction can be performed by the method described in connection with processes l) and m).
If desired, a base of the formula I is reacted with an inorganic or organic acid to transform it into a pharmaceutically suitable acid addition salt, or the base of the formula I is liberated from the acid addition salt using a stronger base.
The pharmacological effect of the novel compounds of the formula I was studied by in vitro and in vivo methods. 8-Methyl-5-(4-aminophenyl)-9H-1,3-dioxolo/4,5-h/-/2,3/benzodiazepine (compound xe2x80x9cAxe2x80x9d) known from HUP No. 191 698 and GB-P No. 2 162 184 was used as the reference substance.
In vitro Determination of AMPA Antagonist Effect
QNTI (inhibition of quisqualate neurotoxicity (test)
The method is based on the phenomenon that the neurotixic effect of quisqualate /i.e. (S)-alpha-amino-3,5-dioxo-1,2,4-oxadiazolidine-2-propanoic acid, an AMPA/kainate agonist/ on the primer telencephalic cell culture of the rat could be inhibited by AMPA/kainate antagonists. The test was performed as described in the literature /Kovxc3xa1cs, A. D., Egyed, A.: Protection against non-NMDA receptor-mediated excitotoxicity by GYKI 52466 in mature telencephalic cultures of the rat, Neurobiology, 4, 59-72 (1996)/. The IC50 values obtained are shown in Table I.
PSI (inhibition of population spike) test
The field potentials (population spike) evoked by electric stimulation of the Shaffer collateral comissural pathway were measured in the CAl neurones of rat hippocampus. The population spike can be inhibited by AMPA/kainate antagonists. The non-cumulative IC50 values are shown in Table I. /Tarnawa, I., Molnxc3xa1r, P., Gaxc3xa1l, L., Andrxc3xa1si, F.: Inhibition of hippocampal field potentials by GYKI 52466 in vitro and in vivo, Acta Physiol. Hung., 79(2), 163-9 (1992)/.
SD (spreading depression) test
The method is based on the phenomenon of spreading depression evoked by kainate in isolated retinal preparation of the chicken. The formation of spreading depression is inhibited (delayed) by AMPA/kainate antagonists. /Sheardown M. J.: The triggering of spreading depression in the chicken retina: a pharmacological study, Brain Res., 607(1-2), 189-194 (1993)/. The obtained IC50 values are shown in Table I.
As shown in Table I, the inhibitory effects of the novel compounds are significantly higher than that of reference compound xe2x80x9cAxe2x80x9d.
In vivo Assays
Acute toxicity
The study was done in NMRI mice of both sexes, weighing 20 to 25 g, with 6 animals in each dose-group. The test compounds were applied at 20 mg/kg volume, and the maximal per os and ip. doses were 500 mg/kg and 300 mg/kg, respectively. The cumulative lethality was recorded on day 7. The animals were kept under standard laboratory conditions. The LD50 values obtained are shown in Table II.
Muscle relaxant effect
The assay was done according to Hoppe in male NMRI mice weighing 20 to 25 g, with 10 animals in each group /Hoppe, J. O., J. Pharmacol. Exp. Ther., 100, 333 (1950)/. Following the ip. treatment of animals, the number of mice showing muscle weakness were recorded at every 10 minutes in the first hour and at half hour intervals afterwards. The animals falling off the 60xc2x0 inclined screen within 30 seconds were considered positive. ED50 values of the given compounds were determined at each time. The duration of effect was defined as the time of last reading when the effect was at least 30%. The results obtained are summarized in Table III.
Although the toxicity and muscle relaxant activity of the novel compounds are similar to that of reference compound xe2x80x9cAxe2x80x9d, the duration of the muscle relaxant effect for Example 73 is substantially longer as shown in Table III.
Maximal electroshock test (MES)
Male NMRI mice weighing 20 to 30 g were used for the method of Swinyard et al. /Swinyard, E. A., Brown, W. C. and Goodman, L.S.: Comparative assays of antiepileptic drugs in mice and rats, J. Pharmacol., 106, 319 (1952)//. The animalsxe2x80x9410 in each groupxe2x80x94were treated ip. either with various doses of the test substance or with vehicle. After 30 minutes, a 50 Hz, 40 mA electroshock was applied for 0.4 s through corneal electrodes. The number of animals that developed tonic extensor convulsion of the hind-limbs was registered, percent inhibition was calculated, and ED50 values were determined by the method of Litchfield and Wilcoxon /Litchfield, J. T., Wilcoxon, F. A.: A simplified method of evaluating dose-effect experiments, J. Pharmacol. Exp. Ther., 96, 99 (1949)/ and summarized in Table IV.
Audiogenic seizure (AS) test
The experiments were carried out by the slightly modified method of De Sarro et al. /De Sarro, G. B., Croucher, M. J. and Meldrum, B. S.: Anticonvulsant action of DS 103-282, Neuropharm., 23, 525 (1984)/. Groups of 8 male DBA/2j strain mice weighing 7 to 14 g were treated ip. with the test substance in 10 ml/kg volume. 15 minutes later, the animals were placed into a covered glass container (30 cm in diameter) and exposed to a 14 kHz 120 dB tone for 60 s at the most. Seizure response was assessed using the following scale: 0=normal behaviour, 1=wild running, 2=clonus, 3=tonic flexor seizure, 4=tonic extensor seizure. The maximum response during the 60 s exposure was recorded for each animal. Lethality was also noted. The ED50 values were determined by the method of Litchfield and Wilcoxon concerning the inhibition of clonic seizures and tonic extensor convulsions. The results are summarized in Table IV.
Global Ischemia Induced by Magnesium Chloride
The experiments were carried out as described by Berga et al. /Berga, P., Beckett, P. R., Roberts, D. J., Llenas, J., Massingham, R.: Synergistic interactions between piracetam and dihydroergocristine in some animal models of cerebral hypoxia and ischemia, Arzneim.-Forsch., 36, 1314-1320 (1986)/. Groups of 10 male NMRI mice weighing 20 to 25 g were treated ip. with the test substance in 10 mg/kg volume. After 30 minutes, saturated aqueous magnesium chloride solution was applied iv. (5 ml/kg) resulting in an immediate cardiac arrest. The elapsed time between the iv. injection and the last gasping was measured (gasping time). The means of the treated groups were expressed as percent of control. Statistical analysis was done by ANOVA followed by DUNCAN test. The dose resulting in 50% descrease in gasping time (ID50) was calculated by linear regression. The results are shown in Table V.
From Table V it is apparant that the ID50 values of the novel compounds of the formula I are significantly lower than that of the reference compound. It is clearly shown that the same extent of neuroprotection can be achieved by significantly lower doses of the novel compounds than that of the reference compound.
Thus, the novel 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives of the formula I can be used as active ingredients of pharmaceutical compositions.
On the basis of the above test results, the novel compounds of the inventionxe2x80x94due to their competitive AMPA/kainate antagonist propertyxe2x80x94have considerable muscle relaxant, neuroprotective and anticonvulsive effects. Consequently, the novel compounds can be used for the treatment of any disease such as epilepsy, diseases resulting in muscle spasm, neurodegenerative diseases, states after stroke, migraine and vomiting, wherein the inhibition of the AMPA/kainate receptors may have a favourable effect.
Moreover, the acute toxicity of the compounds of the formula I is essentially lower than that of the most efficient known AMPA/kainate antagonist 2,3-benzodiazepines. This property renders a significant therapeutical advantage, in contrast to the known compounds, in the treatment of clinical pictures listed above.
The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt or quaternary ammonium derivative thereof and one or more conventional carrier(s).
The pharmaceutical compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethyleneglycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general.
Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington""s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
The pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt or quaternary ammonium derivative thereof. A typical dose for adult patients amounts to 0.1 to 20 mg of the compound of the formula I or a pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof, daily. The above dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e.g. Remington""s Pharmaceutical Sciences.
A preferred subgroup of the pharmaceutical compositions of the invention contains a 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivative or a pharmaceutically suitable acid addition salt or quaternary ammonium derivative thereof, wherein
X represents a carbonyl group or a methylene group, and
R1 stands for a hydrogen atom, a hydroxy group, a methoxy group, an acetoxy group, a methylsulfonyloxy group or a group of the formula xe2x80x94NR4R5, wherein
R4 and R5 mean, independently, a hydrogen atom, a methoxy group, an acetyl group or a C1-4 alkyl group which latter is optionally substituted by a morpholino or an N-(dimethoxyphenylethyl)-N-(methyl)amino group, or
R4 and R5 form with the adjacent nitrogen atom and optionally with a further nitrogen atom or an oxygen atom a saturated or unsaturated heterocyclic group having 5 to 9 members, or
X forms together with R1 a cyano group, a tetrazolyl group or a group of the formula xe2x80x94CHNOH,
R2 stands for a nitro group or an amino group,
R3 represents a hydrogen atom or an acetyl group,
Y is a hydrogen atom, or
Y forms together with R3 a valence bond between the carbon atom in position 8 and the nitrogen atom in position 7,
as the active ingredient.
Within the above preferred subgroup of the invention, the suitable pharmaceutical compositions contain one of the following compounds:
5-(4-aminophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine-8-carboxylic amide,
5-(4-aminophenyl)-8-cyano-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine,
5-(4-aminophenyl)-8-(5-tetrazolyl)-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine,
or a pharmaceutically suitable acid addition salt or a quaternary ammonium derivative thereof as the active ingredient.
A further preferred subgroup of the pharmaceutical compositions of the invention contains a compound of the formula I, wherein
R3 represents a hydrogen atom or a group of the formula xe2x80x94COR7, wherein
R7 stands for a hydrogen atom, a C1-4 alkyl group, a C1-4 alkyl group substituted by 1 to 3 halo atom(s), or a group of the formula xe2x80x94(CH2)nxe2x80x94NR8R9, wherein
R8 and R9 mean, independently, a hydrogen atom, a C1-4 alkyl group optionally substituted by a phenyl group or a morpholino group, and the phenyl group is optionally substituted by one or two methoxy group(s), or
R8 and R9 form, together with the adjacent nitrogen atom and optionally a further nitrogen or oxygen atom a saturated or unsaturated hetero-cyclic group having 5 or 6 members and being optionally substituted by a phenyl group that is optionally substituted by a halo atom or a methoxy group,
n has a value of 0, 1 or 2,
X forms together with R1 a cyano group or a group of the formula xe2x80x94COR6, wherein
R6 represents a hydroxy group or an amino group,
Y stands for a methyl group,
R2 is a nitro group, an amino group, or a (C1-4 alkanoyl)amino group,
or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
Within the latter subgroup, especially preferred pharmaceutical compositions of the invention contain a compound of the formula I, wherein
R3 represents a hydrogen atom or a group of the formula xe2x80x94COR7, wherein
R7 stands for a hydrogen atom, a C1-4 alkyl group, a C1-2 alkyl group substituted by a chloro atom, a trifluoromethyl group, a trichloromethyl group or a group of the formula xe2x80x94(CH2)nxe2x80x94NR8R9, wherein
R8 and R9 represent, independently, a hydrogen atom, a C1-2 alkyl group optionally substituted by a phenyl group or a morpholino group, and the phenyl group is optionally substituted by two methoxy groups, or
R8 and R9 form, together with the adjacent nitrogen atom and optionally a further nitrogen or oxygen atom a pyridinyl, pyrrolidinyl, morpholino or piperazinyl group, wherein the piperazinyl group is substituted by a fluorophenyl or a methoxyphenyl group,
n has a value of 0, 1 or 2,
X forms together with R1 a cyano group,
R2 means an amino group or a (C1-4 alkanoyl)amino group,
Y stands for a methyl group,
or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
Furthermore, the invention refers to a method of pharmaceutical treatment which comprises administering a therapeutically effective non-toxic amount of a 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivative of the formula I or a pharmaceutically suitable acid addition salt or quaternary ammonium derivative thereof to a patient suffering from especially epilepsy or a neurodegenerative disease or being in a state after stroke.
The invention includes also a process for the preparation of a pharmaceutical composition suitable for the treatment of especially epilepsy or a neurodegenerative disease or a state after stroke in which a 8-substituted-9H-1,3-dioxolo/4,5-h/-/2,3/benzodiazepine derivative of the formula I or a pharmaceutically suitable acid addition salt or a quaternary ammonium derivative thereof is converted to a pharmaceutical composition using one or more carrier(s) commonly employed in the manufacture of drugs.